Many patients with mental retardation and dementia have severe abnormalities of higher cortical function. However, many forms of mental retardation (such as Down syndrome) and dementia (such as Huntington disease), do not have striking or consistent histological abnormalities of the cerebral cortex postmortem. This project seeks to define cytopathological changes in cortical neurons using quantitative analysis of cortical cytoarchitecture in Nissl sections, and of dendritic geometry in rapid Golgi impregnations. We will use these methods to examine pyramidal and nonpyramidal neurons in the prefrontal cortex (area 9) and hippocampus (dentate gyrus) in controls and patients with Huntington disease, Down syndrome and other forms of mental retardation. In controls, we will define the geometric characteristics of the nerve cell classes present normally in these areas, and their patterns of change with age. Changes in the normal patterns of cortical cytoarchitecture and dendritic geometry will identify the areas of the cortex and classes of cells that are most vulnerable to these disease states.